In the mammalian central nervous system, L-glutamate serves as a major excitatory neurotransmitter. The interaction of glutamate with its membrane bound receptors is believed to play a role in many important neuronal processes including fast synaptic transmission, synaptic plasticity and long-term potentiation. These processes are fundamental to the maintenance of life and normal human abilities such as learning and memory. Monaghan, D. T. et al., 8 Neuron 267 (1992).
Pharmacological characterization of receptors for L-glutamate has led to their classification into two families based on their biological function: the ionotropic receptors which are directly coupled to cation channels in the cell membrane, and the metabotropic receptors which function through coupling to G-proteins. The present invention concerns a member of the metabotropic family of glutamate receptors.
In addition to its role in normal human physiology, interaction of L-glutamate with its receptors is believed to play a key role in many neurological disorders such as stroke, epilepsy and head trauma, as well as neurode-generative processes such as Alzheimer's disease. Olney, R. W., 17 Drug Dev. Res. 299 (1989). For this reason, understanding the molecular structure of human L-glutamate receptors is important for understanding these disease processes as well as for searching for effective therapeutic agents. Up to the present, the search for therapeutic agents which will bind and modulate the function of human glutamate receptors has been hampered by the unavailability of homo-geneous sources of receptors. The brain tissues commonly used by pharmacologists are derived from experimental animals (non-human) and furthermore contain mixtures of various types of glutamate receptors.
Moreover, in searching for drugs for human therapy, it is obviously desirable to use receptors which are more analogous to those in the intact human brain than are the rodent receptors employed to date. The current invention provides a human receptor which can be used to search selectively for drugs which modulate these receptors.
Recently, four metabotropic receptor subtypes (mGluR1-mGluR4) have been cloned from rat brain. Masu et al., 349 Nature 760 (1991), Houamed et al., 252 Science 1314 (1991) and Tanabe Y. et al. 8 Neuron 169 (1991). In addition, two alternately spliced versions of mGluR1 are known. Tanabe Y. et al. 8 Neuron 169 (1991).
The present invention provides a functional human metabotropic glutamate receptor to the common store of knowledge. The new receptor, called HSmGluR1, will prove especially beneficial to the development of human therapeutic agents.